Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14](=[S:16])[NH2:15])=[CH:10]2)[CH3:3].[C:28]([O:33][CH2:34][CH3:35])(=[O:32])[C:29]#[C:30][CH3:31].C(P(CCCC)CCCC)CCC.O1CCCC1>C1(C)C=CC=CC=1>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]1[S:16][CH:30]([CH2:29][C:28]([O:33][CH2:34][CH3:35])=[O:32])[CH2:31][N:15]=1)=[CH:10]2)[CH3:1]
Reactant: CC#CC(=O)OCC
Reactant: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(N)=S)[nH]c12
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC(C)C)c3[nH]2)S1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 41 %

Procedure:
A mixture of 7-(1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carbothioamide (857 mg), ethyl 2-butynoate (0.6 mL), tributylphosphine (0.6 mL), tetrahydrofuran (10 mL) and toluene (15 mL) was stirred at 60° C. for 1.5 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/99 to 40/60, volume ratio) to give the title compound (381 mg, 41%) as a yellow amorphous solid. MS 517 (MH+).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][N:24]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)[CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Clc1ccccn1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(c3ccccn3)CC2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=563.3 (M+H+), was prepared in accordance with the general method of example 59 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone and 2-chloropyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:28])[CH:15]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.FC1C=CC(N2CCN(C(=O)C(NC(=O)OC(C)(C)C)CC3C=CC=CC=3)CC2)=CC=1>>[ClH:1].[NH2:20][CH:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([N:11]1[CH2:10][CH2:9][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:12]1)=[O:28]
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)C(=O)N1CCN(c2cccc(Cl)c2)CC1
Agent: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)N1CCN(c2ccc(F)cc2)CC1
Product: CC(C)CC(N)C(=O)N1CCN(c2cccc(Cl)c2)CC1
Product: Cl
Yield: 65.7 %

Procedure:
Using 1,1-dimethylethyl 2-(4-(3-chlorophenyl)-1-piperazinyl)-2-oxo-1-(2-methylpropyl)ethylcarbamate in lieu of 1,1-dimethylethyl 2-(4-(4-fluorophenyl)-1-piperazinyl)-2-oxo-1-(phenylmethyl)ethylcarbamate, the procedure of Reference Example 13 was otherwise repeated to provide 1-(2-amino-4-methyl-1-oxopentyl)-4-(3-chlorophenyl)piperazine hydrochloride (1.40 g, 65.7%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20](/[CH:23]=[C:24](/[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)\[C:25]#[N:26])=[CH:19][C:17]=2[CH:18]=1.O.C(OCC)(=[O:37])C.Cl>C(O)C.[OH-].[Na+]>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20](/[CH:23]=[C:24](/[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)\[C:25]([NH2:26])=[O:37])=[CH:19][C:17]=2[CH:18]=1
Reactant: Cc1oc(-c2ccccc2)nc1Cc1cc2cc(/C=C(\C#N)Oc3ccccc3)ccc2o1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1Cc1cc2cc(/C=C(/Oc3ccccc3)C(N)=O)ccc2o1

Procedure:
A solution of (E)-3-[2-(5-methyl-2-phenyl-4-oxazolyl)methyl-5-benzofuranyl]-2-phenoxy-2-propenenitrile (0.19 g, 0.44 mmol) in ethanol (10 ml) and sodium hydroxide (2 ml) was heated to reflux for 24 hours, then cooled, poured into a mixture of water (50 ml) and ethyl acetate and acidified with 6N hydrochloric acid. The layers were separated, the aqueous layer was extracted with ethyl acetate and the combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The product was purified by flash chromatography (hexanes/ethyl acetate/acetic acid, 48:8:1) followed by recrystallization from ethyl acetate/hexanes (30 mg, m.p. 171°-172.5° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:4]=1[CH2:5][NH:6][C:7]1[N:15]=[CH:14][N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][N:11]2[C@H:16]1[C@@H:20]2[O:21]C(C)(C)[O:23][C@@H:19]2[C@@H:18]([CH2:26][N:27]([CH:37]([CH3:39])[CH3:38])[CH:28]2[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([OH:36])=O)[CH2:29]2)[CH2:17]1.C(N(CC)C(C)C)(C)C.[C:55]([C:59]1[CH:60]=[C:61]([NH2:66])[C:62]([NH2:65])=[CH:63][CH:64]=1)([CH3:58])([CH3:57])[CH3:56].C([O-])(O)=O.[Na+]>CN(C)C=O>[NH2:66][C:61]1[CH:60]=[C:59]([C:55]([CH3:57])([CH3:56])[CH3:58])[CH:64]=[CH:63][C:62]=1[NH:65][C:34](=[O:36])[CH2:33][CH2:32][CH:30]1[CH2:31][CH:28]([N:27]([CH2:26][C@H:18]2[CH2:17][C@@H:16]([N:11]3[CH:10]=[N:9][C:8]4[C:12]3=[N:13][CH:14]=[N:15][C:7]=4[NH:6][CH2:5][C:4]3[CH:40]=[CH:41][C:42]([O:44][CH3:45])=[CH:43][C:3]=3[O:2][CH3:1])[C@H:20]([OH:21])[C@@H:19]2[OH:23])[CH:37]([CH3:38])[CH3:39])[CH2:29]1
Reactant: COc1ccc(CNc2ncnc3c2ncn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ncnc3c2ncn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCC(=O)Nc4ccc(C(C)(C)C)cc4N)C3)[C@@H](O)[C@H]2O)c(OC)c1
Reaction time: 2 h
Yield: 91.9 %

Procedure:
N,N,N′,N′-Tetramethyl-0-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (1.19 g, 3.13 mmol) added to a solution of 3-{3-[{[(3aR,4R,6R,6aS)-6-{6-[(2,4-dimethoxybenzyl)amino]-9H-purin-9-yl}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methyl}{isopropyl)amino]cyclobutyl}propanoic acid (1.30 g, 2.09 mmol) and N,N-Diisopropylethylamine (1.20 ml, 6.89 mmol) and 4-tert-butylbenzene-1,2-diamine (0.411 g, 2.50 mmol) in N,N-Dimethylformamide (12.9 ml). The reaction was stirred for 2 hours, NaHCO3 (saturated) was added and the mixture extracted with EtOAc (3×) and the combined organics was dried over MgSO4 filtered and concentrated. The residue was purified by flash chromatography (DCM->DCM/7N NH3 in MeOH 95:5) to yield the desired amide (1.4 g) as a solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH3:9])=[N:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[C:4]([CH2:20][CH3:21])[N:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.CCCCCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][O:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[C:5]1[C:4]([CH2:20][CH3:21])=[N:3][C:2]([C:29]2[CH:28]=[C:27]([F:30])[CH:26]=[CH:25][C:24]=2[O:23][CH3:22])=[C:7]([CH2:8][CH3:9])[N:6]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: CCc1nc(-c2ccc(OC)cc2OC)c(CC)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: COCCOC
Product: CCc1nc(-c2cc(F)ccc2OC)c(CC)nc1-c1ccc(OC)cc1OC
Temperature: 90 °C

Procedure:
Pd(PPh3)4 (8 mg) is added to a solution of 2-chloro-5-(2,4-dimethoxy-phenyl)-3,6-diethyl-pyrazine (70 mg) in DME (2 ml) at room temperature, followed by 2-methoxy-5-fluorophenylboronic acid (45 mg) and Na2CO3 (1M, 0.5 ml). The resulting mixture is heated to 90° C. for 20 hours, then cooled to room temperature. The reaction mixture is diluted with 50% EtOAc in hexane and washed with water and brine, dried, filtered and evaporated. The crude is purified by chromatography (eluted with 15% EtOAc in hexane) to give 2-(2,4-Dimethoxy-phenyl)-3,6-diethyl-5-(5-fluoro-2-methoxy-phenyl)-pyrazine compound 3. MS: 397.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[N:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2
Reactant: COc1ccccc1C=O
Reactant: Cc1ccc2c(N)cccc2n1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccccc1C=Nc1cccc2nc(C)ccc12
Yield: 118.4 %

Procedure:
To 1.74 g (11 mmol) 5-amino-2-methylquinolin and 1.33 ml (11 mmol) 2-methoxybenzaldehyde in 33 ml toluene are added 50 μl acetic acid and 2 g molecular sieve. The mixture is heated over 2 hours under reflux and filtrated through a path of cellites after cooling. The solvent is evaporated and the residue is two times azeothrophed with small portions of toluene. 3.6 g of [1-(2-methoxyphenyl)methylidene]-(2-methylquinolin-5-yl)amine are obtained as a yellow oil. 2.25 ml (26 mmol) 1,1,1-Trifluoroepoxypropane in 38 ml THF and 11 ml hexane are cooled to −100° C. and 15 ml of a 1.6 M n-butyl lithium solution in hexane are added over one hours while the temperature does not exceed −95° C. 10 Minutes after complete addition 3.6 g (11 mmol) raw [1-(2-methoxyphenyl)methylidene]-(2-methylquinolin-5-yl)amine in 49 ml THF are added over one hour while the temperature does not exceed −95° C. After one hour at −100° C. 12 ml diethyl ether are added and the reaction mixture is warmed to −10° C. over one hour. The reaction was quenched by addition of saturated ammonium chloride solution. The phases were separated and the aqueous layer was extracted twice with diethyl ether, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated. Flash chromatography on silica gel (acetone in hexane 0 to 30%) yields 4.27 g {(2-methoxyphenyl)[2-(trifluoromethyl)oxiranyl]methyl}-2-methylquinolin-5-amine as mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1.N1C=CC=CC=1.C(N(CC)C(C)C)(C)C.[CH3:37][O:38][CH2:39]Cl>ClCCl.Cl>[Cl:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([F:12])=[C:6]([S:8]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[CH2:37][O:38][CH3:39])(=[O:10])=[O:9])[CH:7]=1
Reactant: Nc1ccc(F)cn1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Reactant: COCCl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCN(c1ccc(F)cn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Temperature: 0 °C
Reaction time: 16 h

Procedure:
5-Chloro-2,4-difluorobenzenesulfonyl chloride (1 g, 4 mmol) in dichloromethane (7.6 mL) was added portion-wise to a solution of 2-amino-5-fluoropyridine (498 mg, 4.44 mmol) in pyridine (7.6 mL, 94 mmol) cooled to 0° C. After addition was complete, the reaction mixture was warmed to room temperature. After 16 hours, the reaction mixture was diluted with dichloromethane and hydrochloric acid (1 N aqueous solution). The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water, diluted with ethyl acetate, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in dichloromethane (8.0 mL) and N,N-diisopropylethylamine (0.776 mL, 4.45 mmol) added. The mixture was cooled to 0° C. and chloromethyl methyl ether (0.338 mL, 4.45 mmol) was added dropwise by syringe. The reaction mixture was warmed to room temperature and after stirring for 6 hours, the reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo onto Celite™. The residue was purified by automated flash chromatography (24 g silica gel column) eluting with ethyl acetate:hexanes (gradient 0:1 to 1:0, by volume) to afford the title compound, 363 mg.
Reaction SMILES: I[C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([CH3:19])[CH:13]=2)[CH:3]=1.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][C:24]#[CH:25])[CH3:21]>>[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][C:24]#[C:25][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([CH3:19])[CH:13]=2)[CH:3]=1)[CH3:21]
Reactant: Cc1cc(Oc2ccnc3cc(I)sc23)ccc1N
Reactant: C#CCN(CC)CC
Product: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(N)c(C)c3)c2s1

Procedure:
Prepared from 4-(2-iodothieno[3,2-b]pyridin-7-yloxy)-2-methylbenzenamine (0.250 g, 0.556 mmol), and N,N-diethylprop-2-yn-1-amine (0.0680 g, 0.612 mmol), according to the procedure for Example 6, Step B. The crude was purified by Biotage 40S (EtOAc). The product was an orange oil (116 mg, 39%). LRMS (ESI pos) m/e 366 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1.S(=O)(=O)(O)O.[CH3:15]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:15])=[O:8])[S:5][CH:6]=1
Reactant: CO
Reactant: O=C(O)c1cc(Br)cs1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)cs1
Temperature: 50 °C
Reaction time: 96 h
Yield: 97 %

Procedure:
To a solution of 4-bromo-2-thiophenecarboxylic acid (25 g, 121 mmol) in methanol (241 ml) was added sulfuric acid (32 ml, 604 mmol). The resulting solution stirred at 50° C. over 4 d. The solution was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly without further purification providing methyl 4-bromo-2-thiophenecarboxylate (26 g, 118 mmol, 97% yield), LCMS (ES) m/e 222 (M+H)+.
Reaction SMILES: [C:1](/[C:4](/[C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:5]\[NH:6][C:7]([NH2:9])=O)(=[O:3])[CH3:2].O=P(Cl)(Cl)[Cl:18]>O>[Cl:18][C:7]1[N:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:4]([C:1](=[O:3])[CH3:2])=[CH:5][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)/C(=C\NC(N)=O)C(=O)C(F)(F)F
Solvent: O
Product: CC(=O)c1cnc(Cl)nc1C(F)(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 41.9 %

Procedure:
A mixture of compound (E)-1-(2-acetyl-4,4,4-trifluoro-3-oxobut-1-en-1-yl)urea (55 g, 0.25 mol) and POCl3 (240.7 g, 1.57 mol) was stirred at 100° C. for 3 h. The mixture was added dropwise to water (1.5 L) at rt and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography eluting with PE/EtOAc 3/1 to give compound 1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (23.5 g, 42.7% yield) as a pale-yellow oil. 1H NMR (CDCl3 300 MHz): δ 8.80 (s, 1H), 2.58 (s, 3H). 19F NMR (920-083-1A CDCl3 400 MHz): δ-65.5 ppm. 13C NMR (903-158-1A CDCl3 400 MHz): δ 195.9, 162.3, 160.1, 153.8 (dd, J=50 Hz), 130.9, 119.5 (dd, J=366 Hz), 30.7.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH2:12])[N:3]=1.CCN(CC)CC.[F:20][C:21]1([F:36])[O:25][C:24]2[CH:26]=[CH:27][C:28]([C:30]3([C:33](Cl)=[O:34])[CH2:32][CH2:31]3)=[CH:29][C:23]=2[O:22]1>ClCCl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:33]([C:30]2([C:28]3[CH:27]=[CH:26][C:24]4[O:25][C:21]([F:36])([F:20])[O:22][C:23]=4[CH:29]=3)[CH2:32][CH2:31]2)=[O:34])[N:3]=1
Reactant: Nc1cc2ccccc2c(Br)n1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cc2ccccc2c(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.6 %

Procedure:
To a solution of 1-bromoisoquinolin-3-amine (3.00 g, 13.5 mmol) and Et3N (3.8 mL, 27 mmol) in dichloromethane (50 mL) was added a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (4.18 g, 13.5 mmol) in dichloromethane (50 mL). The resulting reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was then washed with 1N aqueous NaOH (2×200 mL), 1 N aqueous HCl (1×200 mL) and saturated aqueous NaHCO3 (1×200 mL). The organics were dried over sodium sulfate and evaporated. The resulting material was purified by silica gel chromatography eluting with 0-50% ethyl acetate/hexanes to yield N-(1-bromoisoquinolin-3-yl)-1-(2,2-difluorobenzo[d][1,3]-dioxol-5-yl)cyclopropanecarboxamide (4.2 g, 70%). ESI-MS m/z calc. 446.0. found 447.1 (M+1)+. Retention time 2.39 minutes.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([F:10])=[N:8][CH:9]=1)=[N+:2]=[N-:3].[C:11](OC=C)(=O)[CH3:12]>>[N:1]1([C:4]2[CH:5]=[CH:6][C:7]([F:10])=[N:8][CH:9]=2)[CH:12]=[CH:11][N:3]=[N:2]1
Reactant: C=COC(C)=O
Reactant: [N-]=[N+]=Nc1ccc(F)nc1
Product: Fc1ccc(-n2ccnn2)cn1
Temperature: 100 °C

Procedure:
5-Azido-2-fluoropyridine (262 mg, 1.9 mmol) and vinyl acetate (4.0 mL, 43 mmol) were mixed in a flame dried high pressure sealable vessel. The reaction vessel was evacuated and charged with nitrogen, sealed, and heated to 100° C. for 15 hours. The reaction was cooled to room temperature and TLC indicated that the reaction was complete. Minimal dichloromethane was added to the reaction (just enough to dissolve solids that formed upon cooling) and the solution directly chromatographed on silica gel (Biotage size 40S column), eluting with 20-50% ethyl acetate/heptane to give the title compound as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]([NH:11][NH2:12])=[CH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[CH:27]=O.[CH:29]([C:31]1[S:35][C:34]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:33][C:32]=1[CH3:44])=O>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[CH2:27][N:12]1[C:29]([C:31]2[S:35][C:34]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[N:33][C:32]=2[CH3:44])=[C:9]2[C:10]([N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:6](=[O:15])[N:7]([CH3:14])[C:8]2=[O:13])=[N:11]1
Reactant: O=Cc1ccnc2ccc(Cl)cc12
Reactant: Cn1c(=O)cc(NN)n(CC2CC2)c1=O
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1C=O
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12

Procedure:
This compound was made following the procedure described above, starting with 1-(cyclopropylmethyl)-6-hydrazino-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 6-chloroquinoline-4-carbaldehyde, followed by tert-butyl 5-formyl-4-methyl-1,3-thiazol-2-ylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[OH:30])[C:23]([NH:25][NH2:26])=[O:24].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CCOC(C)=O.C1COCC1>[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[OH:30])[C:23]([NH:25][NH:26][C:12](=[O:14])[C@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:18])[C@H:15]([OH:17])[CH3:16])=[O:24]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Reactant: NNC(=O)c1ccc(O)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(O)c(Cl)c2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: -20 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
To a 50 mL round bottom flask was added (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (1.00 g, 3.73 mmol, 1.0 equiv.) and anhydrous THF (18.7 mL). After the flask was flushed with nitrogen, 3-chloro-4-hydroxybenzoic hydrazide (766 mg, 4.11 mmol, 1.1 equiv.) was added. The stirring solution was cooled to −20° C., and 1-hydroxybenzotriazole (HOBt) (555 mg, 4.11 mmol, 1.1 equiv.) was added in one portion, followed by 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDC) (1.79 g, 9.33 mmol, 2.5 equiv.) and then triethylamine (TEA) (2.08 mL, 14.9 mmol. 4.0 equiv.). The solution was stirred at −20° C. for 1 h and gradually warmed to room temperature overnight. The contents of the flask were filtered over Celite® in a ground glass fritted funnel to remove solids formed during the reaction. The solution was diluted with 50 mL of EtOAc. The EtOAc solution was washed with 5% citric acid solution (w/v) (2×50 mL), distilled water (2×50 mL), and brine (1×50 mL). The organic layer was dried over Na2SO4 and then concentrated in vacuo to yield a light yellow solid. The product was purified via automated flash chromatography (0→50% EtOAc/hexanes 100% EtOAc, 24 g of silica gel; TLC Rf=0.38, 100% EtOAc, vanillin stain) to provide the desired product as an off-white solid (870 mg, 53% yield). Other data: 1H NMR (400 MHz, acetone-d6, δ in ppm) 7.96 (d, J=2.2 Hz, 1H), 7.79 (dd, J=2.19, 8.49 Hz, 1H), 7.53 (d, J=8.65 Hz, 1H), 7.105 (d, J=8.5 Hz, 1H), 6.72 (d, J=8.65 Hz, 1H), 5.58 (d, J=7.18 Hz, 1H), 4.22 (m, 1H), 4.11 (dd, J=5.13, 7.18 Hz, 1H), 2.35 (s, 3H), 1.37 (d, J=6.45 Hz, 3H); LRMS (ESI−) exact mass calcd for C19H18Cl2N4O4 [M]+ 437.28, found 438.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:10][CH2:11][CH2:12][Cl:13])=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: Fc1ccc(S)cc1
Product: Fc1ccc(SCCCCl)cc1

Procedure:
Prepared by Procedure R and Scheme Z using 4-fluorobenzenethiol and 1-bromo-3-chloropropane.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][CH:6]1[CH2:10][CH2:9][C:8]2([C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]2([CH3:19])[OH:18])[O:7]1.CN(C)C1C=CC=CC=1.OS(O)(=O)=O>CCOCC>[C:1]([O:18][C:11]1([CH3:19])[CH2:12][CH2:13][CH2:14][C:15]([CH3:17])([CH3:16])[C:8]21[O:7][CH:6]([CH3:5])[CH2:10][CH2:9]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC1CCC2(O1)C(C)(C)CCCC2(C)O
Agent: O=S(=O)(O)O
Solvent: CN(C)c1ccccc1
Solvent: CCOCC
Product: CC(=O)OC1(C)CCCC(C)(C)C12CCC(C)O2
Reaction time: 48 h

Procedure:
5.9 g (0.079 M) of acetyl chloride were added over 30 minutes at 20° to a mixture of 2,6,10,10-tetramethyl-1-oxa-spiro[4.5]decan-6-ol -- isomer A; see Example 1 -- and 10.9 g of N,N-dimethylaniline. After having been kept for 2 days at room temperature the reaction mixture was heated to reflux during 3 hours, then cooled and treated with 50 ml of ether. The reaction mixture was then filtered and the clear filtrate thus obtained poured onto crushed ice and finally acidified with a 10 % aqueous solution of H2SO4. The organic layer was then washed with NaHCO3 in water, dried, evaporated and subjected to a fractional distillation to give 2.5 g of a product having b.p. 90° - 100°/0.1 Torr. After crystallisation in aqueous ethanol 1.9 g (75%) of the desired ester were isolated -- isomer A.